The present invention relates to diphenylalkylamine derivatives, which have affinity for the opioid xcex4 receptor and are useful in the medicinal field, and relates to medicaments comprising said compounds as an active ingredient.
Opioid receptors are mainly classified into three types, i.e., xcexc, xcex4 and xcexa from a viewpoint of differences in pharmacological actions. On the basis of the discovery of an endogenous opioid peptide in 1970""s, some progresses were made in studies about their mechanism of action. In 1990""s, studies about opioid receptor structures advanced based on genetic analysis, and their mechanism of action has been being elucidated by the molecular biology. As also for the xcex4 receptor, based on the success of cloning of xcex4 receptor by Evans, Kieffer et al. in 1992, many studies have been vigorously performed in the medicinal and pharmaceutical fields by the molecular biology.
Although higher order functions of the opioid xcex4 receptors have not yet been successfully elucidated, those already reported include that an opioid xcex4 receptor agonist exhibits analgesic activity (D. E. Moulin et al., Pain, 1985, 23, 213), and that the opioid xcex4 receptor agonist has a reducing effect on adverse reactions induced by an opioid xcexc receptor agonist and an opioid xcexa receptor agonist (Gallingan et. al., J. Pharm. Exp. Ther. 1984, 229, 641). Since the opioid xcex4 receptor is known to be present widely in the central and peripheral nerve systems and considered to have a wide variety of functions, discovery of an effective and selective opioid xcex4 receptor ligands can greatly contribute to therapeutic treatments of central nerve system diseases including schizophrenia, depression, cerebral apoplexy, epilepsy, Alzheimer""s disease, and Parkinson""s disease, and peripheral nerve system diseases including pains (Exp. Opin. ther. Patents, 1999, 9, 353).
Compounds related to the general formula (I) of the present invention are reported in J. Med. Chem. 1994, 37, 2125, WO93/15062, WO96/36620, WO97/10230, WO98/28270, WO98/28275 and the like. The compounds described in J. Med. Chem. 1994, 37, 2125 and WO93/15062 have very high affinity for xcex4 receptors. However, these compounds have not been used clinically, because their productions are difficult due to three asymmetric centers, which are apparent from their chemical formulas, and they have poor pharmacokinetics. Derivatives having a structure with no asymmetric center are reported in WO96/36620, WO97/10230, WO98/28270, WO98/28275 and the like. However, their affinities for the xcex4 receptor are undesirably lowered compared to the compounds described above. Thus, no compound has been reported which has a structure with no asymmetric center and high affinity for the xcex4 receptor.
Further, among the compounds relevant to the compounds of the general formula (I) of the present invention, derivatives that do not have a partial structure represented by X have been reported in WO94/11337, WO97/44329, WO98/43942 and the like. However, as for these compounds, affinity for xcex4 receptor has not been reported.
An aim of the present invention is to provide a substance having affinity for the opioid xcex4 receptor, in particular, to provide an effective and selective opioid xcex4 receptor ligand. A further aim is to provide a medicament useful for preventive and/or therapeutic treatment of central nerve system diseases and peripheral nerve system diseases on the basis of the features.
In the specification, the term xe2x80x9copioid xcex4 receptor ligandxe2x80x9d means a compound having an ability to bind to an opioid xcex4 receptor, and comprehensively includes an agonist, antagonist, partial agonist, and inverse agonist for an opioid xcex4 receptor.
In order to achieve the aim described above, the inventors of the present invention studied variety of compounds. As a result, they found that compounds represented by the following general formula (I) had high affinity for the opioid xcex4 receptor, and achieved the present invention.
The present invention thus provides compounds represented by the following general formula (I): 
[in the formula, X represents the following group (II), (III), (IV), (V), or (VI), 
n represents 1, 2 or 3,
R1 and R2 each independently represent a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, a lower alkoxy group which may be substituted, or a hydroxy group, or represent xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94 as xe2x80x94R1xe2x80x94R2xe2x80x94,
R3 represents a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, a lower alkoxy group which may be substituted, a hydroxy group, a cyano group, an amino group which may be substituted, a carbamoyl group which may be substituted, a carboxyl group, a (substituted or unsubstituted lower alkoxy)carbonyl group, or a (substituted or unsubstituted lower alkyl)carbonyl group,
R4 represents a saturated or unsaturated monocyclic or bicyclic carbocyclic group or a monocyclic or bicyclic heterocyclic group containing one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom,
R5, R6, R7, R8, R9, R10, R11 and R12 each independently represent a hydrogen atom, a lower alkyl group which may be substituted, or a lower alkenyl group which may be substituted, and R3 and R4, R5 and R6, R7 and R8, and R9 and R10 may bind to each other to form a cyclic structure] or salts thereof.
The present invention further provides medicaments comprising a substance selected from the group consisting of the compounds represented by the general formula (I) and pharmacologically acceptable salts thereof as an active ingredient. The preferred medicaments consist of a pharmaceutical composition comprising the substance described above and an additive for pharmaceutical preparations. These medicaments are useful for preventive treatment and/or therapeutic treatment of central nerve system diseases or peripheral nerve system diseases.
The present invention further provides an opioid xcex4 receptor ligand comprising a substance selected from the group consisting of the compounds represented by the general formula (I) and pharmacologically acceptable salts thereof.
The present invention still further provides use of substances selected from the group consisting of the compounds represented by the general formula (I) and pharmacologically acceptable salts thereof for manufacture of the medicaments and methods for preventive treatment and/or therapeutic treatment of central nerve system diseases or peripheral nerve system diseases, which comprises the step of administering a preventively and/or therapeutically effective amount of a substance selected from the group consisting of the compounds represented by the general formula (I) and pharmacologically acceptable salts thereof to a mammal including human.
The entire disclosures of Japanese Patent Application No. 2000-085202 are incorporated by reference in the disclosures of the specification.
Novel compounds of the present invention will be explained in more detail.
In the specification, a xe2x80x9clower alkyl groupxe2x80x9d or a xe2x80x9clower alkoxy groupxe2x80x9d as a substituent, or a xe2x80x9clower alkyl groupxe2x80x9d or xe2x80x9clower alkoxy groupxe2x80x9d constituting a part of a substituent means an alkyl or alkoxy group in a straight or branched chain, cyclic form, or any combination thereof having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, cyclopentyl, n-hexyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy and the like. Similarly, a xe2x80x9clower alkenyl groupxe2x80x9d as a substituent means a straight, branched, or cyclic alkenyl group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and examples thereof include vinyl group, allyl group and the like. In a group containing an alkenyl moiety, the number of double bonds contained in the alkenyl moiety is not particularly limited, and a double bond contained in the alkenyl moiety may either be in Z- or E-configuration.
The term xe2x80x9chalogen atomxe2x80x9d means a fluorine atom, chlorine atom, bromine atom, or iodine atom unless otherwise specifically mentioned.
The term xe2x80x9chetero atomxe2x80x9d means, for example, a hetero atom such as an oxygen atom, nitrogen atom, or sulfur atom unless otherwise specifically mentioned, preferably an oxygen atom, nitrogen atom, or sulfur atom. A xe2x80x9cheterocyclic ringxe2x80x9d may contain two or more hetero atoms as ring-constituting atoms. In such compounds, two or more hetero atoms may be the same or different. A heterocyclic group means a residue of a heterocyclic ring obtained by removing one or more hydrogen atoms that bind to ring-constituting atoms.
In the formula (I), R5 and R6 in the group (II), R7 and R8 in the group (III), and R9 and R10 in the group (TV), which groups are represented by X, may each independently bind to each other to form a cyclic structure. Examples of the ring include aziridine, azetidine, pyrrolidine, or piperidine, and an example of a preferred ring includes piperidine. An unsaturated bond may exist in a part of these rings.
Further, R5, R6, R7, R8, R9, R10, R11, and R12 in the group (II), (III), (IV), (V), or (VI) represented by X preferably each independently represent a hydrogen atom or a lower alkyl group, or R5 and R6 preferably bind to each other to form piperidine. The group represented by X is preferably the group (II).
The integer represented by n is preferably 2 or 3.
R1 and R2 preferably represent a hydrogen atom, a halogen atom, a lower alkoxy group, or a hydroxy group, or represent xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94 as xe2x80x94R1xe2x80x94R2xe2x80x94. R1 and R2 most preferably represent a hydrogen atom, a fluorine atom, a methoxy group, or a hydroxy group.
R3 is preferably a hydrogen atom or a lower alkylcarbonyl group, and most preferably a hydrogen atom.
Examples of the carbocyclic ring constituting the saturated or unsaturated monocyclic or bicyclic carbocyclic group represented by R4 include rings of cyclopentane, cyclohexane, benzene, indane, naphthalene and the like, and a preferred example includes benzene.
Examples of the heterocyclic ring constituting the monocyclic or bicyclic heterocyclic group containing one or more hetero atoms represented by R4 include rings of imidazole, benzofuran, indole, benzothiophene, benzothiazole, benzoxazole, benzimidazole, benzotriazole, benzisothiazole, benzisoxazole, quinoline, isoquinoline, quinazoline, pyridinoimidazole, benzoxazine and the like, and preferred examples include indole and benzimidazole.
An unsaturated bond as a part of the saturated or unsaturated monocyclic or bicyclic carbocyclic group or the monocyclic or bicyclic heterocyclic ring containing one or more hetero atoms represented by R4 may be hydrogenated to form a saturated bond, or may be oxidized to form a cyclic ketone, cyclic amide (lactam), cyclic ester (lactone) or cyclic ureide structure. A substituting position of the adjacent piperidine ring may be any substitutable position.
One or more hydrogen atoms on the saturated or unsaturated monocyclic or bicyclic carbocyclic group or the monocyclic or bicyclic heterocyclic ring containing one or more hetero atoms represented by R4 may be substituted. Examples of the substituent include a lower alkyl group such as methyl group, a lower alkoxy group such as methoxy group, a lower alkenyl group such as allyl group, a halogen atom, a hydroxy group, a cyano group, an amino group, a N-(lower alkyl)amino group such as N-methylamino group, a N,N-di(lower alkyl)amino group such as N,N-dimethylamino group, a nitro group, a carbamoyl group, a N-(lower alkyl)carbamoyl group such as N-methylcarbamoyl group, a N,N-di(lower alkyl)carbamoyl group such as N,N-dimethylcarbamoyl group, a carboxyl group, a lower alkoxycarbonyl group such as methoxycarbonyl group, a lower alkylcarbonyl group such as acetyl group, an oxo group, a benzyl group, a hydroxymethyl group and the like. Preferred substituents are a lower alkyl group, an oxo group, a benzyl group, and a hydroxymethyl group, and particularly preferred substituents are a lower alkyl group, an oxo group, and hydroxymethyl group. When two or more substituents exist, they may be the same or different. Positions of substituents are not limited, and they can exist at any substitutable positions.
Further, an example of the compounds wherein R5 and R6 bind to each other to form a cyclic structure include the compounds in which a spiro ring is formed. Specifically, examples include the following groups (VII) and (VII) (In the following chemical formulas, a spiro ring is formed in each upper ring. In the formulas, each of two solid lines drawn from a ring represents a single bond that binds to the 3- or 5-position of the piperidine ring on which R3 and R4 substitute). 
[in the groups, R13 and R15 each independently represent a hydrogen atom, a lower alkyl group which may be substituted, or a lower alkenyl group which may be substituted, and
R14 and R16 each independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted lower alkyl group, a lower alkenyl group which may be substituted, a lower alkoxy group which may be substituted, a hydroxy group, a cyano group, an amino group which may be substituted, a nitro group, a carbamoyl group which may be substituted, a carboxyl group, a (substituted or unsubstituted lower alkoxy)carbonyl group, or (substituted or a unsubstituted lower alkyl)carbonyl group]
The definition that a group represented by R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 or R16 xe2x80x9cmay be substitutedxe2x80x9d means that the group may have any kind of one or more of substituents. When the groups have two or more substituents, they may be the same or different. The positions of the substituents are not limited, and they can exist at any substitutable positions. Kinds of the substituents are not limited, and examples include a lower alkyl group such as methyl group, a lower alkoxy group such as methoxy group, a lower alkenyl group such as allyl group, a halogen atom, a hydroxy group, a cyano group, an amino group, a N-(lower alkyl)amino group such as N-methylamino group, a N,N-di(lower alkyl)amino group such as N,N-dimethylamino group, a nitro group, a carbamoyl group, a N-(lower alkyl)carbamoyl group such as N-methylcarbamoyl group, a N,N-di(lower alkyl)carbamoyl group such as N,N-dimethylcarbamoyl group, a carboxyl group, a (lower alkoxy)carbonyl group such as methoxycarbonyl group, a (lower alkyl)carbonyl group such as acetyl group, and a saturated or unsaturated 3- to 6-membered carbocyclic group such as cyclopropyl, cyclopentyl, cyclohexyl and phenyl (these carbocyclic groups may have one or more substituents, and examples of the substituents include a lower alkyl group such as methyl group, a lower alkoxy group such as methoxy group, a lower alkenyl group such as allyl group, a halogen atom, a hydroxy group, a cyano group, an amino group, a N-(lower alkyl)amino group such as N-methylamino group, a N,N-di(lower alkyl)amino group such as N,N-dimethylamino group, a nitro group, a carbamoyl group, a N-(lower alkyl)carbamoyl group such as N-methylcarbamoyl group, a N,N-di(lower alkyl)carbamoyl group such as N,N-dimethylcarbamoyl group, a carboxyl group, a (lower alkoxy)carbonyl group such as methoxycarbonyl group, a (lower alkyl)carbonyl group such as acetyl group and the like), and a phenyl group is preferred.
Among the compounds represented by the general formula (I), examples of preferred class of compounds include those wherein R4 represents a residue of a ring selected from a group consisting of benzene, indole, and benzimidazole (a part of unsaturated bonds of the ring may be hydrogenated to form a saturated bond(s), or the ring may be substituted).
Another preferred class of compounds include those wherein R3 and R4 form a cyclic structure and represent the following group (VII) or (VIII): 
[in the groups, R13, R15, R14 and R16 have the same meanings as defined above].
More preferred class of compounds include those wherein X represents the group (II), (III), (IV), (V) or (VI),
n is 2 or 3,
R1 and R2 each independently represent a hydrogen atom, a halogen atom, a lower alkoxy group, or a hydroxy group, or R1 and R2 represent xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94 as xe2x80x94R1xe2x80x94R2xe2x80x94,
R3 is a hydrogen atom or a lower alkylcarbonyl group,
R4 is a residue of a ring selected from the group consisting of benzene, indole, and benzimidazole (a part of unsaturated bonds of the ring may be hydrogenated to form a saturated bond(s), and a hydrogen atom on the ring may be substituted with an oxo group, a lower alkyl group, a hydroxymethyl group, or a benzyl group), or R3 and R4 bind to each other to form a cyclic structure of a ring selected from imidazole, N-phenylimidazolidine, and isoquinoline (a hydrogen atom on the ring may be substituted with an oxo group or a lower alkyl group), and
R5, R6, R7, R8, R9, R10, R11, and R12 each independently represent a hydrogen atom or a lower alkyl group, or
R5 and R6 bind to each other to form piperidine.
Further preferred class of compounds include those wherein X represents the group (II).
In the present invention, among the compounds represented by the general formula (I), particularly preferred compounds are as follows.
1. 1-[3-(4-Diethylcarbamoylphenyl)-3-(3 -methoxyphenyl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2 -on-1-yl)piperidine
2. 1-[3-(4-Diethylcarbamoylphenyl)-3-(3 -hydroxyphenyl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2 -on-1-yl)piperidine hydrochloride
3. 8-[3-(4-Diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one
4. 1-[3-(4-Diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine
5. 1xe2x80x2-[3-(4-Diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propyl]-2,3-dihydro-5-methylspiro[isoquinoline-4(1H),4xe2x80x2-piperidin]-1-one
6. 1xe2x80x2-[3-(4-Diethylcarbamoylphenyl)-3-(3-hydroxyphenyl)propyl]-2,3-dihydro-5-methylspiro[isoquinoline-4(1H),4xe2x80x2-piperidin]-1-one hydrochloride
7. 1-[3-(4-Diethylcarbamoylphenyl)-3-(2-methoxyphenyl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine
8. 8-[3-(4-Diethylcarbamoylphenyl)-3-(2-methoxyphenyl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one
9. 1xe2x80x2-[3-(4-Diethylcarbamoylphenyl)-3-(2-methoxyphenyl)propyl]-2,3-dihydro-5-methylspiro[isoquinoline-4(1H),4xe2x80x2-piperidin]-1-one
10. 1-[3-(4-Diethylcarbamoylphenyl)-3-(2-methoxyphenyl)propyl]-4-(2-hydroxymethyl-1 H-benzimidazol-1-yl)piperidine
11. 1-[3-(4-Diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propyl]-4-(1H-benzimidazol-1-yl)piperidine
12. 1-[3-(4-Diethylcarbamoylphenyl)-3-(4-methoxyphenyl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine
13. 1-[3-(4-Diethylcarbamoylphenyl)-3-(4-hydroxyphenyl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine hydrochloride
14. 1-[3-(4-Diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propyl]-4-(2-methyl-1H-benzimidazol-1-yl)piperidine
15. 1-[3-(4-Diethylcarbamoylphenyl)-3-(2-hydroxyphenyl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine hydrochloride
16. 1-[3-(3-Diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine
17. 1-[3-(4-Diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propyl]-4-(3-benzyl-1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine
18. 1-[3-(4-Diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propyl]-4-(3-cyclopropylmethyl-1,3-dihydro-2 H-benzimidazol-2-on-1-yl)piperidine
19. 1-[4-(4-Diethylcarbamoylphenyl)-4-(3-methoxyphenyl)butyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine
20. 1-[3-(4-Diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propyl]-4-(3,3-dimethyl-2,3-dihydro-1 H-indol-2-on-1-yl)piperidine
21. 1-[3-(4-Diethylcarbamoylphenyl)-3-(3-fluorophenyl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine
22. 8-[3-(4-Diethylcarbamoylphenyl)-3-(3-hydroxyphenyl)propyl]-8-phenyl-1,3,8-triazaspiro[4,5]decan-4-one hydrochloride
23. 1-[3-(4-Diethylcarbamoylphenyl)-3-(1,3-benzodioxole-5-yl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine
24. 1-[4-(4-Diethylcarbamoylphenyl)-4-(3-hydroxyphenyl)butyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine hydrochloride
25. 1-[3-(4-Diethylcarbamoylphenyl)-3-(3,4-dihydroxyphenyl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on- 1-yl)piperidine hydrochloride
26. 1-[3-(4-Diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propyl]-4-1H-indol-3-yl)-piperidine
27. 1-[3-(4-Diethylcarbamoylphenyl)-3-(3-hydroxyphenyl)propyl]-4-(1H-indol-3-yl)-piperidine hydrochloride
28. 1-[3-(4-Diethylcarbamoylphenyl)-3-(3-hydroxyphenyl)propyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine hydrochloride
29. 1-[3-(4-Diethylcarbamoylphenyl)-3-phenylpropyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine
30. 1-[3-(4-Diisopropylcarbamoylphenyl)-3-(3-methoxyphenyl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine
31. 1-[3-(4-Diethylcarbamoylphenyl)-3-(4-fluorophenyl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2 -on-1-yl)piperidine
32. 1-[3-(4-Piperidinocarbonylphenyl)-3-(3-methoxyphenyl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on- 1-yl)piperidine
33. 1-[3-(4-Diethylcarbamoylphenyl)-3-(3-hydroxyphenyl)propyl]-4-(1H-benzimidazol-1-yl)piperidine hydrochloride
34. 1-[3-(4-Carboxylphenyl)-3-(3-methoxyphenyl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine hydrochloride
35. 4-(1,3-Dihydro-2H-benzimidazol-2-on-1-yl)-1-[3-(4-methoxycarboxylphenyl)-3-(3-methoxyphenyl)propyl]piperidine
36. 4-Acetyl-1-[3-(4-diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propyl]-4-phenylpiperidine
37. 1xe2x80x2-[3-(4-Diethylaminosulfonylphenyl)-3-(3-methoxyphenyl)propyl]-2,3-dihydro-5-methylspiro[isoquinoline-4(1H),4xe2x80x2-piperidin]-1-one
38. 2,3-Dihydro-5-methyl-1xe2x80x2-[3-[4-(1-methylbutyryl)phenyl]-3-(3-methoxyphenyl)-propyl]spiro[isoquinoline-4(1H),4xe2x80x2-piperidin]-1-one
39. 1-[3-(4-Diethylaminomethylphenyl)-3-(3-methoxyphenyl)propyl]-4-(1H-benzimidazol-1-yl)piperidine
Methods for preparing the novel compounds of the present invention will be explained in more detail. The novel compounds of the present invention can be prepared by the methods described below. 
[in the formulas, R1, R2, R3, R4, X and n have the same meanings as defined in the general formula (I), and W represents a halogen atom excluding a fluorine atom or represents a leaving group such as p-toluenesulfonyloxy group, methanesulfonyloxy group, or trifluoromethanesulfonyloxy group].
The compounds (IX) can be prepared by the method described in WO97/10230 with partial modification, and a specific preparation thereof is described later in Reference Example 1.
The compounds (X) can be obtained as commercially available reagents, or can also be obtained by a known method or an improved method thereof.
The compounds (I) according to the present invention can be obtained by a reaction of a compound (IX) and a compound (X) in a solvent that is not involved in the reaction (for example, dichloromethane, tetrahydrofuran, methyl ethyl ketone, N,N-dimethylformamide, dimethyl sulfoxide and the like) in the presence of a base (for example, pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate, sodium carbonate and the like) at a reaction temperature of which lower limit is 20xc2x0 C. and upper limit is 100xc2x0 C., preferably lower limit is 20xc2x0 C. and upper limit is 50xc2x0 C., for a reaction time of which lower limit is 2 hours and upper limit is 48 hours, preferably lower limit is 16 hours and upper limit is 24 hours.
In the synthesis of the compounds of the present invention, purification of a target compound from a reaction mixture is performed by methods ordinarily used in the filed of organic chemistry, for example, by distribution of reaction products between water and an organic solvent that is not freely miscible with water (e.g., benzene, toluene, ethyl acetate, butyl acetate, methyl isobutyl ketone, chloroform, dichloromethane and the like) for extraction, and then by concentration, crystallization and the like. Further, as required, fractionation purification by column chromatography using alumina, silica gel or the like, for example, may also be performed.
The compounds of the present invention may be in the form of a salt. The salt may be an acid addition salt such as salts with inorganic acids including hydrochloric acid, nitric acid, hydrobromic acid, and sulfuric acid, salts with aliphatic monocarboxylic acids, dicarboxylic acids, hydroxyalkanoic acids, hydroxydialkanoic acids, amino acids and the like, or salts deriving from non-toxic organic acids such as aromatic acids, aliphatic acids, and aromatic sulfonic acid. Examples of such acid addition salts include hydrochloride, hydrobromide, nitrate, sulfate, hydrogensulfate, hydrogenphosphate, dihydrogenphosphate, acetate, propionate, tartrate, oxalate, malonate, succinate, fumarate, maleate, mandelate, benzoate, phthalate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, lactate, malate, glycolate, trifluoroacetate and the like.
Typical compounds of the present invention are specifically explained in detail in the examples of the present specification. Therefore, those skilled in the art can prepare any compound falling within the scope of the general formula (I) based on explanations of the general preparation methods describer above and examples described later by appropriately choosing starting compounds, reagents, reaction conditions and the like, and if necessary, applying appropriate modifications or alterations to the methods disclosed in the examples.
As well as the compounds in free form or salts thereof, any hydrates and solvates thereof also fall within the scope of the present invention. The types of solvents that form the solvates are not particularly limited. Examples include solvents such as methanol, ethanol, acetone, and diethyl ether. However, the solvents are not limited to these examples.
The compounds of the present invention may have one or more asymmetric carbon atoms depending on the type of substituent, and any of stereoisomers such as optically active isomers or diastereoisomers in a pure form, any mixtures of the stereoisomers, racemates and the like also fall within the scope of the present invention.
The compounds of the present invention are characterized to have affinity for opioid xcex4 receptor. Therefore, the compounds of the present invention are useful for preventive and/or therapeutic treatment of central nerve system diseases such as schizophrenia, depression, cerebral apoplexy, epilepsy, Alzheimer""s disease, and Parkinson""s disease and peripheral nerve system diseases such as pains, in which the opioid xcex4 receptor is involved.
The medicaments provided by the present invention are characterized to comprise at least one kind of the compound represented by the general formula (I) or pharmacologically acceptable salt thereof as an active ingredient. The medicaments of the present invention can be administered to human or animals other than human by any of oral or parenteral routes (for example, intravenous injection, intramuscular injection, subcutaneous administration, rectal administration, percutaneous administration, intraspinal administration). As the medicaments of the present invention, the substances as active ingredients, per se, may be administered. It is generally preferable to prepare and administer a pharmaceutical composition, as a form suitable for the administration route, by using one or more kinds of additives for pharmaceutical preparations.
Specifically, examples of orally available formulations include tablets, capsules, powders, granules, syrups and the like. Examples of parenteral formulations include injections such as intravenous and intramuscular injections, formulations for rectal administration, oily suppositories, aqueous suppositories and the like.
These various pharmaceutical preparations can be prepared by using additives for pharmaceutical preparations which are ordinarily used, for example, excipients, disintegrating agents, binders, lubricants and coloring agents.
Examples of the excipients include lactose, glucose, cornstarch, sorbit, crystalline cellulose and the like. Examples of the disintegrating agents include starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, dextrin and the like. Example of the binders include dimethylcellulose, polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, gelatin, hydroxypropylcellulose, polyvinylpyrrolidone and the like. Examples of the lubricants include talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oil and the like. Further, the pharmaceutical preparations can be prepared with addition of a buffer, pH modifier, stabilizer or the like as required.
Although content of the compound of the present invention in the pharmaceutical composition may vary depending on types of formulations. Generally, its lower limit is about 0.1% by weight and upper limit is 50% by weigh, preferably lower limit is 0.5% by weight and upper limit is 20% by weight based on the total composition. A dose may appropriately be determined depending on each case in consideration of the age, body weight, sex, type of a disease, severity of symptoms of a patient and the like. Generally, its lower limit is 1 mg and upper limit is 1000 mg, preferably its lower limit is 1 mg and upper limit is 300 mg, per day for an adult. The dose is administered once a day or several times a day dividedly.